Since high-speed computers became generally available in the sixties, three lines of research have been developing and unconsciously converging in a way that promises to make huge changes in how certain kinds of drug research can be done. These methodologies are X-ray crystallography, quantitative structure-activity relationships (QSAR) and computer graphics. Kraut's lab in La Jolla can now determine difference maps on our inhibitors bound to the enzyme dihydrofolate reductase (DHFR) in weeks. We have the coordinates of three of our inhibitors as well as several standard inhibitors and six more of ours should be completed by this summer. Langridge's lab in San Francisco (UCSF) has achieved a breakthrough in the development of three-dimensionsal color graphics which enormously aids the interpretation of ligand-protein (or DNA) X-ray crystallographic data. We have arranged to cooperate with these two groups using DHFR as a means to develop basic drug design. Our labs are being supplied with highly purified DHFR by Kaufman at NIH, Poe at Merck, and soon by Freisheim at Cincinnati. Knowing what occurs in isolated enzymes i only part of the problem. Almost no evidence is available to show whether or not the QSAR on isolated receptor (enzyme) is the same as that of receptor in the living cells. For this more difficult level of drug design we are cooperating with Khwaja's lab at USC to test inhibitors on tumor cells, and Coats in Cincinnati has completed testing a set of our inhibitors on two bacterial cells: L. casei sensitive to methotrexate (MTX) and L. casei resistant to MTX. We have found both similarities and distinct differences between the QSAR of purified enzyme and enzyme in living cells. This cooperative effort between several labs, each expert in certain complex areas, creates a condition not available even in the largest drug companies.